5-hydroxy and 5-amino-1,2-dihydro-3H-benzo[e]indoles are known to be very potent cytotoxins. Examples of these compounds are illustrated below as the 5-hydroxy compound A; (Boger & Johnson, Angew. Chem. Int. Ed. Engl., 1996, 35, 1438) and the 5-amino compound B; (Atwell et al., J. Org Chem., 1998, 63, 9414).

These compounds have IC50s in cell culture in the low nM range. It has also been shown that both the 5-hydroxy-(Boger et al., Tetrahedion, 1991, 47, 2661) and the 5-amino (Gieseg et al., AntiCancer Drug Design, 1999, 14, 77) compounds bind in the minor groove of DNA and alkylate at the N3 of adenine in a highly regio- and sequence-selective manner. A number of analogues of the 5-hydroxy compounds have been reported in the literature, where the 5-hydroxy group has been protected as a carbamate. For potency to be expressed the carbamate is cleaved by rapid and non-specific specific enzymatic hydrolysis releasing the corresponding phenol. These compounds include carzelesin (C; Li et al., Cancer Res., 1992, 52, 4904)
and KW-2189 (D; Kobayashi et al., Cancer Res., 1994, 54, 2404).

The lability of these carbamates in plasma would be desirable for systemic release of a drug. However, in contrast to the rapid and non-specific cleavage of these carbamates, the corresponding carbamates of the 5-amino chloromethyl benzoindoles (CBIs) such as for example compound E; (Hay et al., Bioorg. Med. Chem. Lett., 1999, 15; 2237)
have been found to be stable and relatively non-toxic until the nitro group is reduced by a localized enzymatic-activated step that causes the fragmentation of the cytotoxic 5-aminoCBI. The minor aerobic nitroreductase (NTR) from E. coli (Parkinson et al., J. Med. Chem., 2000, 43, 3624) might for example be used for the enzymatic-activated step. The 5-amino compounds are thus of interest as potent cytotoxins (Atwell et al., J. Med. Chem., 1999, 42, 3400), and also for the formation of prodrugs for GDEPT (Hay et al., Bioorg. Med. Chem. Lett., 1999, 15, 2237).
The reported (Atwell et al., J Org Chem., 1998, 63, 9414) 15-step synthesis of the 5-amino compounds is from 1-hydroxynaphthalene-2-carboxylic acid, employing a nitro group as a protecting group for the eventual 5-amino group and gives the 5-amino compound B in only a 3% overall yield. The synthetic scheme is not straightforward and includes some difficult synthetic steps.
It is therefore an object of the invention to provide a synthetic method that provides better yields for these 5-aminoCBI compounds, or to at least provide the public with a useful alternative.